DESCRIPTION (Applicant's Abstract): The long term goal of this study is to elucidate the molecular mechanisms of axonal targeting during development and plasticity in the adult in the mesencephalic dopaminergic system, which plays key roles in mediating drug dependence and brain reward. The neural structures in the dopamine system are interconnected topographically. Dopaminergic neuron in the ventral tegmental area (VTA) project primarily to the ventromedial striatum (which include the nucleus accumbens, olfactory tubercle and ventromedial portion of the caudate putamen), while neurons in the substantia nigra (SN) project to dorsolateral striatum (which corresponds to dorsolateral caudate putamen). Although the topographic relations have been known for nearly two decades, and appear to be critical for physical and psychological dependence on drugs, the molecular basis for this topographic projection is unknown. It has been proposed that topographic mapping is accomplished by matching gradients of chemoaffinity labels on the presynaptic and postsynaptic neurons. Consistent with this proposal, we have shown Elk, and Eph family receptor, and its ligand, Lerk5, are expressed in complementary patterns in the ventral tegmental area/substantial nigra, and the targets, nucleus accumbens/caudate-putamen. Furthermore, we have shown that Lerk5 is unregulated by cocaine treatment in adult mice. Previous studies conducted in our laboratory and in others have shown that interactions between Eph ligands and receptors expressed in complementary gradients specify the topographic projection maps in the brain. Together, these observations led to the hypothesis that Elk and its ligand regulate axonal targeting and plasticity in the ascending dopaminergic system. To test this hypothesis and examine the roles of Elk and Lerk5 in the ontogeny of the dopamine system, we propose to first examine the spatial and temporal patterns of expression of Elk and its ligand during the development of projection. We will also study the biological effects of Lerk5 on the VTA/SN dopaminergic neurons in vitro using a co-culture assay we have developed. Furthermore, the expression of Elk and Lerk5 expression in vitro will be altered using transgenic technology to examine the effects on the development of the ascending dopamine system. To study whether Elk and Lerk5 also play roles in drug-induced plasticity, we will examine how drug treatment alters their expression in the adult. Understanding the molecular basis governing the axonal connections and modifications may shed new light on the underlying mechanism of drug addiction, as well as diseases involving this system such as Parkinson's disease.